Pharmacological manipulation of neurotransmitter metabolism has been a powerful tool in the treatment of nervous and mental diseases. Many advances in psychopharmacology have resulted from our basic knowledge of neurotransmitter synthesis and degradation. The broad objective of the proposed research is to elucidate the metabolic control mechanisms which regulate the degradation of the amino acid neurotransmitter, gamma-amino butyric acid (GABA). It is currently thought that there are two possible alternative mechanisms by which brain GABA levels and the flux of metabolites through the pathway may be regulated. In the first of these, control is mediated primarily by the kinetic properties of the enzymes in the pathway. According to the second proposed mechanism, control is exerted by a combination of kinetic regulation of the enzyme which synthesizes GABA, glutamate decarboxylase, and the equilibrium position of the degradative reaction catalyzed by GABA-2-oxoglutarate transaminase and succinic semialdehyde dehydrogenase. According to this mechanism, the position of the equilibrium catalyzed by the latter enzyme is determined by the state of the mitochondrial NAD redox couple. The proposed work is a new approach to GABA metabolism which is designed to distinguish between these alternative metabolic control mechanisms and to test the effects of changes in the mitochondrial NAD redox state on brain levels of GABA. In addition, the effects of selected psychopharmacological agents which affect GABA metabolism by unknown mechanisms will be studied in terms of the mitochondrial NAD redox state and the equilibrium position of the degradative reactions. The results of these studies may provide new pharmacological methods of manipulating brain levels of neurotransmitters.